Denture detergents containing antimicrobial metal ions

ABSTRACT

The present invention provides a novel microbicide for a detergent comprising an inorganic carrier conjugated with an antimicrobial metal ion, and a denture detergent containing said microbicide.

TECHNICAL FIELD

The present invention relates to a microbicide for detergents and to adenture detergent comprising the microbicide.

BACKGROUND ART

It is important to prevent microbial contamination by a detergent havingmicrobicidal effect for keeping sanitary life environment, andtherefore, microbicides useful for detergents are greatly necessitated.Such microbicides have been presently used in various detergents.

Microbicide is generally required to satisfy the conditions that itexhibits microbicidal effect extensively on various microorganisms innature, that it is effective in a small amount, and that it isnon-toxic, non-stimulative and safe to a living body. In the case thatthe microbicide is used in combination with a detergent, such as amicrobicide for detergents, it would be further required that it isstable in a detergent formulation, that its microbicidal effect is notinhibited by pH and other ingredients, and that it does not spoil thefunction, color and flavor of the detergent, in addition to therequirements above described.

Microbicides are often used in a denture detergent, which is a sort ofdetergents, like in other detergents. Since it is difficult tocompletely remove the indigenous microbiota in mouth only by the actionof the detergent, these indigenous microbiota are usually sterilized bythe action of a microbicide contained in a denture detergent. One of theserious problems for users of dentures is “peculiar halitosis”, and suchhalitosis is caused by proliferation of the indigenous microbiota inmouth. One of the indigenous microbiota in mouth, Candida albicans, isalso a pathogen of denture stomatitis. Thus, in view of prevention ofthe halitosis and denture stomatitis, it is greatly important to use amicrobicide in a denture detergent. Microbicides contained incommercially available denture detergents are active oxygen generatingagents, such as peroxides, or enzymes, and denture cleaning is conductedby using one of them alone or in combination of two or more of them.

Although it has been studied for finding a microbicide that can exhibithigher microbicidal effect within shorter time compared to theabove-mentioned conventional microbicides for denture detergents,practically usable microbicide has not yet been found. The main reasonof said less usable microbicide is due to the inhibition of themicrobicidal effect of the microbicide by the interaction with otheringredient(s) in a detergent. For example, in the case that sodiumlauryl sulfate, which is preferably and widely used as a detergentingredient in mouthwashes and denture detergents, is used as a detergentingredient together with a cationic microbicide such as cetylpyridiniumchloride and dequalinium chloride, they react with each other to form awhite insoluble material, which results in inhibition of themicrobicidal effect. In the case that sodium lauryl sulfate is used as adetergent ingredient together with a microbicidal ingredient such assodium salicylate, phenyl salicylate, and the like, they would not causeinhibition of the microbicidal effect. However, when this combination isused in a denture cleaning, it will provide rather unpleasant feelingthan refreshing feeling in the mouth of the denture user after thedenture cleaning.

When a nonionic surfactant, such as Amisol MDE, Amisol LME, Emulgen 950and Emulgen PP-290, is used as a detergent ingredient in combinationwith a microbicide such as cetylpyridinium chloride, which is inert tothe surfactant, the detergent cannot exhibit sufficient detergent andeffervescent effects contrary to a detergent containing sodium laurylsulfate, and hence, it cannot achieve to desired detergent function.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a microbicide fordetergents exhibiting excellent microbicidal effect within shorter timein comparison with conventional microbicides for detergents, withoutinhibition of the microbicidal effects by other ingredient in thedetergent, and a denture detergent comprising said microbicide. It isanother object of the present invention to provide a microbicide fordetergents, which does not inhibit the action of a detergent comprisingsodium lauryl sulfate having superior detergent and effervescenteffects. It is yet another object of the present invention to provide adenture detergent, which has a superior microbicidal effect with keepingthe excellent detergent and effervescent actions of sodium laurylsulfate, and is comfortably used.

The present inventors have extensively studied to achieve the objectsdescribed above and found that an inorganic carrier conjugated with anantimicrobial metal ion, which may be hereinafter referred to as “themicrobicide of the invention”, is extremely superior as a microbicidefor detergents. Thus, the microbicide of the invention has superiormicrobicidal effect, and it exhibits the superior microbicidal effectwithin a short time since the microbicidal effect is not inhibited byother ingredients in the detergent.

Thus, the present invention provides a microbicide for detergentscomprising an inorganic carrier conjugated with an antimicrobial metalion. Furthermore, the present invention provides a denture detergentcomprising an inorganic carrier conjugated with an antimicrobial metalion.

Inorganic carriers conjugated with an antimicrobial metal ion have beenhitherto mixed with materials such as synthetic resins, rubbermaterials, paints, synthetic fiber and papers for the purpose ofenhancing the antimicrobial property of these materials. Suchantimicrobial materials have been used in various fields, such aselectric home appliances, house furnishings, office supplies, buildingmaterials, wrappings, medical supplies, and the like. However, thepresent inventors have first found that such inorganic carriersconjugated with an antimicrobial metal ion are effective for improvingthe microbicidal property of a detergent and exhibit their microbicidaleffect on a subject to be cleaned.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the microbicidal effect of each microbicide onCandida.

FIG. 2 is a graph showing the microbicidal effect of each microbicide onStreptcoccus pneumoniae.

FIG. 3 is a graph showing the microbicidal effect of each microbicide onStaphylococcus aureus.

BEST MODE FOR CARRYING OUT THE INVENTION

The first embodiment of the invention is a microbicide for detergentscomprising an inorganic carrier conjugated with an antimicrobial metalion.

Although the microbicide for detergents of the invention can be used forany detergent, preferred detergent intended by the present invention isa denture detergent.

The antimicrobial metal ion to be used for conjugation with an inorganiccarrier includes silver, copper, and zinc ion. Preferred antimicrobialmetal ion is silver ion. The inorganic carrier to be used forconjugating with an antimicrobial metal ion of the invention includes,for example, calcium phosphate, calcium silicate, calcium carbonate,aluminum phosphate, zirconium phosphate, zeolite, silica gel, etc.Preferred inorganic carrier of the invention is calcium phosphate,aluminum phosphate, zirconium phosphate or zeolite. More preferredinorganic carrier is hydroxyapatite, calcium phosphate, or calciumhydrogen phosphate. Further preferred inorganic carrier ishydroxyapatite, or tricalcium phosphate. Most preferred inorganiccarrier is hydroxyapatite.

The inorganic carrier conjugated with an antimicrobial metal ion can beprepared according to the methods as described in literatures. Forexample, when the inorganic carrier is calcium phosphate, silicate orcarbonate, it can be prepared by substantially the same method asdescribed. in Japanese Patent Publication No. 218765/1991, which isherein incorporated by reference. Briefly, it is prepared by adsorbing asalt of an antimicrobial metal on a pulverized inorganic carrier, andcalcining the resultant at a temperature that the inorganic carriershrinks so that the metal is not desorbed from the inorganic carrierinto water.

When the inorganic carrier is tricalcium phosphate, it can be preparedaccording to the method as described in Japanese Patent Publication No.84870/1997, which is herein incorporated by reference. Briefly, it canbe prepared conjugating an antimicrobial metal ion on tricalciumphosphate by means of adsorption or ion exchange, or alternatively byproducing tricalcium phosphate from an aqueous solution of a solublecalcium salt (e.g., calcium chloride) and disodium hydrogen phosphate orammonium hydrogen phosphate under an ammonia alkaline condition in thepresence of an antibacterial metal salt.

The inorganic carrier conjugated with an antimicrobial metal ion iscommercially available in various forms. Commercially availableinorganic carriers conjugated with an antimicrobial metal ion include,for example, Silverace A-903K (trade name of calcium phosphatemanufactured by Taihei Chemical Industrial Co., Ltd.), Novaron AGZ330(trade name of zirconium phosphate manufactured by Toagosei Co., Ltd.),Rasap AN-600SA (trade name of aluminum phosphate manufactured by RasaIndustries, Ltd.), Apacider AK (trade name of hydroxyapatitemanufactured by Sangi Co., Ltd.), Zeomic AW10D (trade name of zeolitemanufactured by Shinanen Co., Ltd.), Amenitop VerIII (trade name ofcomplex compound silver thiosulfato.silica gel manufactured byMatsushita Electric Industrial Co., Ltd.), etc.

The inorganic carrier conjugated with an antimicrobial metal ion of theinvention is most preferably Apacider. Apacider is a hydroxyapatiteconjugated with silver ion, and several grades of products different inspecifications and particle diameters, etc. are commercially available,such as Apacider AW (general grade, calcined form); Apacider A25(special grade, calcined form); Apacider NB (special grade, non-calcinedform); Apacider AK (microparticle grade, calcined form). Most preferredmicrobicide for detergents of the invention is a commercially availableproduct in the name of Apacider AK (Sangi Co., Ltd.; microparticlegrade, calcined form, average particle diameter: 0.3 μm).

The second embodiment of the invention is a denture detergent comprisingthe micorobicide for detergent of the invention. The denture detergentof the invention contains the microbicide for detergents in an amount of0.05-10% by weight, preferably 0.1-3% by weight based on the weight ofthe denture detergent. If the amount is less than the above range, ithas less microbicidal activity and cannot achieve the intended object.On the other hand, when the microbicide is contained in an amount largerthan the above range, it is not preferable to use in formulating into atablet, because the resultant tablet would decrease in its hardness tocause capping during a tabletting process, and further abrasion orclacking during a distribution of the product.

The denture detergent of the invention can be formulated into variousforms such as effervescent tablets, effervescent granules, effervescentpowders, liquids, and teeth pastes. Preferred formulation is aneffervescent tablet.

The denture detergent of the invention may further contain a detergentingredient, a bleaching ingredient, an effervescent ingredient, and anactive oxygen generating material, etc., in addition to the microbicideof the invention. The term “coated”, as used herein for the ingredientscontained in the denture detergent of the invention, means that theingredient is coated with an appropriate coating agent to avoidinteraction with other ingredients coexisting in the formulation. Forexample, the terms “coated sodium percarbonate” and “coated citric acid”refer to sodium percarbonate and citric acid coated with an adequatecoating agent, respectively. The coating method may be any conventionalcoating methods. For instance, coating may be conducted simultaneouslywith a granulation step by means of spray granulation, rollinggranulation or the like, or after the granulation step by pan coating,flow coating, dry coating or the like. The detergent ingredients includealkyl sulfate salts such as sodium lauryl sulfate, triethanolaminelauryl sulfate, sodium cetyl sulfate, sodium lauroyl sarcosinate, sodiumdi-2-ethylhexylsulfosuccinate, sodium lauryl phosphate,alkylbenzenesulfonate, α-olefin sulfonate and the like. Especially,sodium lauryl sulfate is preferable, since it has superior detergenteffect on tobacco tar, etc., and its detergent effect can be visuallyand psychologically realized from effervescence, and it does not provideunpleasant feeling in mouth after using. The microbicide for detergentof the invention does not give undesired decrease of microbicidal effectdue to interactions among ingredients, contrary to the case ofcombination of cetylpyridium chloride and sodium lauryl sulfate, sincethe microbicide for detergents of the invention does not react withsodium lauryl sulfate. The combination of the microbicide of theinvention and sodium lauryl sulfate is very preferable in that themicrobicide ingredient and the detergent ingredient can satisfactorilyexhibit their superior microbicidal, detergent and effervescent effects,respectively. The detergent ingredient is usually used in an amount of1-30% by weight, preferably 1-20% by weight. In case of sodium laurylsulfate, it is used in an amount of 1-15% by weight, preferably 3-10% byweight.

For the bleaching ingredients, the combination of a peroxide such assodium perborate, sodium percarbonate, or the like, and sodiumperoxysulfate or potassium hydrogen monopersulfate (e.g., OXONE;manufactured by Du Pont) can be used as an active oxygen generatingagent. Alternatively, a chlorine microbicide (e.g., sodium hypochlorite,sodium dichloroisocyanuate, sodium trichloroisocyanurate, etc.), sodiumpercarbonate or OXONE may be used. Optionally, the bleaching ingredientsmay be coated with a coating agent. A preferred coating agent is amixture of a magnesium, alkali metal or calcium salt of an aromatichydrocarbon sulfonic acid, a sulfate ester of an alkyl aromatic hydroxyhydrocarbon ethylene oxide adduct, higher fatty acid alcohol sulfateester or a sulfate ester of a higher fatty acid alcohol ethylene oxideadduct, and an alkali silicate, carbonate, bicarbonate or sulfate. Apreferred bleaching ingredient is a combination of a coated sodiumpercarbonate and OXONE. The coated sodium percarbonate preferably coatedby a mixture of an alkali metal salt of an aromatic hydrocarbon sulfonicacid and an alkali silicate salt. The bleaching agent is used in anamount of 20-70% by weight, preferably 30-60% by weight. When thecombination of a coated sodium percarbonate and OXONE is used, theamount of the former is in the range of 15-45%, preferably 25-40% byweight, and the amount of the latter is in the range of 5-20%,preferably 5-15% by weight.

For the effervescent ingredient, a combination of a carbonate orbicarbonate such as sodium hydrogen carbonate, sodium carbonate,potassium hydrogen carbonate, and an organic acid such as citric acid,succinic acid, sulfamic acid or an inorganic acid is used. Optionally,the acid may be coated with a coating agent. A preferred coating agentis acetyl cellulose, gum arabic, sodium alginate, soluble starch,hydroxy propyl cellulose, wheat starch, food polysaccharides such assucrose, lactose and the like. A preferred effervescent ingredient is acombination of a coated citric acid and sodium hydrogen carbonate. Afood saccharide is especially preferable as a coating agent of thecoated citric acid. The amount of the effervescent ingredient is in therange of 5-30% by weight for a carbonate or bicarbonate and in the rangeof 5-45% by weight for an organic or inorganic acid. Preferably, acarbonate or bicarbonate is used in an amount of 8-25% by weight, and anorganic or inorganic acid is used in an amount of 10-40% by weight. Whena coated citric acid and sodium hydrogen carbonate are used, the amountof the former is in the range of 10-40% by weight, preferably 15-35% byweight, and the amount of the latter is in the range of 5-25%,preferably 8-20% by weight.

In addition to the above ingredients, the denture detergent of theinvention may contain a lubricant such as silicon dioxide, syntheticaluminum silicate, magnesium carbonate, magnesium stearate, talc,calcium stearate, hydrogenated castor oil or magnesium hydroxide in anamount of 0.1-3% by weight, preferably 0.3-2% by weight. Preferably,synthetic aluminum silicate is added in an amount of 0.1-3% by weight,more preferably 0.3-1.5% by weight.

Also, the denture detergent of the invention may further contain astabilizing agent such as sodium sulfite, sodium edetate, magnesiumchloride, calcium citrate, magnesium oxide or sodium thiosulfate in anamount of 0.5-15% by weight, preferably 1-10% by weight. Preferably,magnesium oxide is added in an amount of 1-5% by weight, more preferably1.5-3% by weight.

Further, a humectant (e.g., propylene glycol, polyethylene glycol,sorbitol, glycerol, glycerol monostearate, polysorbate 80, liquidpetrolatum), a solubilizing agent (e.g., hydrogenated castor oil,vestibule oils, polyoxyethylene nonylphenyl ether, sugar ester), aflavor (e.g., saccharin sodium, menthol, peppermint oil, spearmint oil,herbmint oil), and a colorant may optionally be added. Preferably, thedenture detergent of the invention contains 3-20% by weight, preferably5-15% by weight, of polyethylene glycol as a humectant, 0.5-3% byweight, preferably 0.8-2.0% by weight, of hydrogenated castor oil as asolubilizing agent, 0.5-3% by weight, preferably 0.5-1.5% by weight, ofpeppermint oil as a flavor, 0.01-0.05% by weight, preferably 0.01-0.03%by weight, of food dye as a colorant.

EXAMPLES

The present invention is described in detail with reference to thefollowing experiments and examples, and also, the effect of theinvention is demonstrated.

Example 1 Tests of the Microbicidal Effect by the Microbicide forDetergents of the Invention

Various inorganic carriers conjugated by silver ion as shown in Table 1(commercial products), which can be used as a microbicide for detergentsof the invention, were used in the test for evaluation of theirmicrobicidal effect.

TABLE 1 Kind of the Trade Name Manufacturer carrier Apacider AK SangiCo., Ltd. hydroxyapatite Silverace A-903K Taihei Chemical calciumphosphate Industrial Co., Ltd. Rasap AN-600SA Rasa Industries, Ltd.aluminum phosphate Novaron AGZ330 Toagosei Co., Ltd. zirconia phosphateZeomic AW10D Shinanen Co., Ltd. zeolite Amenitop Ver-III MatsushitaElectric Industrial Co., Ltd. silica gel

Microorganism

a) Candida albicans A (Candida)

b) Streptcoccus pneumoniae ATCC 49619 (Streptcoccus pneumoniae)

c) Staphylococcus aureus IFO 3060 (Staphylococcus aureus)

Test Method

A microorganism-containing solution (10⁷ CFU/mL) (1 mL) was added to anaqueous solution of a microbicide (0.01 w/v %) (100 mL), and the mixturewas then incubated by stirring with a stirrer (200 rpm) at ambienttemperature. Number of the microorganism in the solution was determinedby a plate dilution test (fiber antimicrobial activity test) at eachtime.

Result

Change of the number of the microorganism with time is shown in FIG. 1(Candida), FIG. 2 (Streptcoccus pneumoniae) and FIG. 3 (Staphylococcusaureus). The microbicidal activity is shown by D value (the time(minute) when the number of the microorganism is decreased to {fraction(1/10)}), which was calculated by the following equation. Obtainedvalues are shown in Table 2.

D=1/k

k: a constant of death rate =1/t log₁₀N₀/N_(t)

t: treating time (minutes)

N₀: initial number of the microorganism

N_(t): number of the survival microorganism after t minutes

TABLE 2 D value of various inorganic microbicides StreptcoccusStaphylococcus Candida pneumoniae aureus Apacider AK 65.6 0.6≧ 21.3Silverace A-903K 176.7 0.6≧ 11.9 Rasap AN-600SA 37.0 0.6≧ 11.1 NovaronAGZ330 176.7 0.6≧ 22.2 Zeomic AW10D 23.9 0.6≧ 6.1 Amenitop Ver-III1010.0 0.6≧ 66.7

Zeomic (zeolite), Rasap (aluminum phosphate) and Apacider(hydroxyapatite) exhibited superior microbicidal effects on Candida andStaphylococcus aureus. Silverace (calcium phosphate) exhibited asuperior antimicrobial effect on Staphylococcus aureus. All thesemicrobicides exhibited excellent microbicidal effects on Streptcoccuspneumoiae.

Example 2 Formulation

A denture detergent containing 0.50% by weight of Apacider AK as amicrobicide is prepared using the following ingredients:

TABLE 3 Ingredient % by weight coated citric acid B 30.00 coated sodiumpercarbonate (PC-NS) 31.00 OXONE (2KHSO₅.KHSO₄.K₂SO₄) 8.00 sodium laurylsulfate 5.00 sodium hydrogen carbonate 10.60 hydrogenated castor oil1.00 food dye 0.02 peppermint oil 0.88 polyethylene glycol 10.00synthetic aluminum silicate 1.00 magnesium oxide 2.00 Apacider AK 0.50Total 100.00

The above ingredients are mixed and compressed to form a tablet.

Example 3 Test for the Microbicidal Effect by the Denture Detergent

The denture detergent (3 g) of the invention prepared in Example 2 andthe denture detergents A, B and C manufactured by other companies wereeach dissolved in 200 mL of water (so as to 1.5% aqueous solution), ofwhich the microbicidal effects were tested.

Test Samples

(1) Denture detergent of the invention. (as prepared in Example 2)

(2) Denture detergent A

(3) Denture detergent B

(4) Denture detergent C

Note) these denture detergents A, B and C manufactured by othercompanies have the microbicidal effects by active oxygen.

Microorganism

a) Candida albicans A (Candida)

b) Streptcoccus pneumoniae ATCC 49619 (Streptcoccus pneumoniae)

c) Staphylococcus aureus IFO 3060 (Staphylococcus aureus)

Test Method

1. Preparation of a Microbe-applied Plate

The microorganism was inoculated in Trypto-soya broth, and subjected tostationary culture at 35° C. for 48 hours. The culture broth wascentrifuged (9,000 rpm for 10 minutes) to collect the cells, and theretowas added a sterilized water (20 mL) to prepare a microbial suspension.

The microbial suspension was diluted so that its absorbance became inthe range of 0.0750≧Abs≧0.0350 to prepare a dipping solution. A standardcurve was previously prepared, on which the range corresponding to 10⁵CFU/mL was predetermined.

Toughron DE (Miki Chemical Product Co., Ltd.) was heated to polymerize,which was then cut in a size of 1.5×2.0 cm (0.2 cm in thickness) toprepare a resin plate. This plate was sterilized, followed by dipping inthe dipping solution as prepared above at 25° C. for 3 hours to obtain amicrobe-applied plate.

2. Evaluation of Microbicidal Effect

One tablet of the above denture detergent was each placed on the bottomof a 200 mL-graduated cylinder. A microbe-applied plate as preparedabove was hanged in each cylinder, and tap water (200 mL) wasimmediately added thereto. The plate was taken out at each timepredetermined. The plate was washed once with 20 mL of sterilized water,which was then incubated in a test tube containing Trypto-soya broth (15mL) at 35° C. for 72 hours. The presence of microorganism was determinedby checking the culture broth. It was determined by microscopicallyobserving a turbid culture broth and identifying the microorganism usinga selective medium.

Result

The time when the microorganism was no more detected in the culturebroth, i.e., complete death time, was determined, and result for eachmicroorganism is shown in Table 4. The longest time among those obtainedfrom three independent experiments for each microorganism is shown inthe table as the complete death time.

TABLE 4 Streptcoccus Staphylococcus Candida pneumoniae aureus Denturedetergent of 15 5 20 the invention Denture detergent A 20 5 25 Denturedetergent B 25 5 45 Denture detergent C 25 5 40

The denture detergent of the invention and the denture detergents A, Band C manufactured by other companies all exhibited superiormicrobicidal effects on Streptococcus pneumoniae, and their completedeath times were within 5 minutes. For Candida and Staphylococcusaureus, the complete death time thereof by the denture detergent of theinvention was both within 20 minutes, and the denture detergent of theinvention thus exhibited superior microbicidal effect.

These results showed that the denture detergent of the invention hasmicrobicidal effects greater than those of the denture detergentsmanufactured by other companies.

What is claimed is:
 1. A denture detergent comprising 10-40% by weightof citric acid, 15-45% by weight of sodium percarbonate, 5-20% by weightof potassium hydrogen monopersulfate, 5-25% by weight of sodium hydrogencarbonate, 0.01-0.05% by weight of food dye, 1-15% by weight of sodiumlauryl sulfate, 0.5-3% by weight of hydrogenated castor oil, 3-20% byweight of polyethylene glycol, 0.5-3% by weight of peppermint oil,0.1-3% by weight of synthetic aluminum silicate, 1-5% by weight ofmagnesium oxide and 0.05-10% by weight of an inorganic carrierconjugated with an antimicrobial metal ion.
 2. The denture detergent ofclaim 1 which is an effervescent tablet.
 3. The denture detergent ofclaim 1, wherein the antimicrobial metal ion is silver, copper and/orzinc ion.
 4. The denture detergent of claim 1, wherein the antimicrobialmetal ion is silver ion.
 5. The denture detergent of claim 1, whereinthe inorganic carrier is a phosphate, a silicate or a carbonate.
 6. Thedenture detergent of claim 5, wherein the phosphate is hydroxyapatite ortricalcium phosphate.
 7. The denture detergent of claim 5, wherein thephosphate is hydroxyapatite.
 8. The denture detergent of claim 1,wherein the inorganic carrier conjugated with an antimicrobial metal ionis in an amount of 0.1-3% by weight.
 9. The denture detergent of claim1, wherein the inorganic carrier conjugated with an antimicrobial metalion is in an amount of 0.1-0.5% by weight.